α-oxoacyl amino-caprolactam derivative

ABSTRACT

The purpose of the present invention is to provide a pharmaceutical composition that is useful for the treatment of diseases that are caused by an increase in bone resorption and that does not cause serious side effects even when used in combination with another drug. The present invention relates to: an α-oxoacyl aminocaprolactam derivative that is represented by formula (I) 
                         
(in the formula, X is —O— or —N(R 1 )— and R 1  represents an alkoxycarbonyl group having 1-10 carbon atoms); and a bone resorption inhibitor containing the α-oxoacyl aminocaprolactam derivative.

RELATED APPLICATIONS

This application is the U.S. national stage pursuant to 35 U.S.C. §371,of Japanese international application Ser. No. PCT/JP2014/003158, filedJun. 13, 2014 and published in Japanese on Dec. 18, 2014 as publicationWO2014/199644 A1, which claims the benefit of priority of JapaneseApplication No. 2013-125181, filed Jun. 14, 2013, which are herebyexpressly incorporated by reference in their entirety.

TECHNICAL FIELD

The present invention relates to a novel α-oxoacylaminocaprolactamderivative. Specifically, the present invention relates to anα-oxoacylaminocaprolactam derivative having the effect of selectivelyinhibiting cathepsin K, which is the principal cysteine proteaseparticularly involved in bone resorption.

BACKGROUND ART

In recent years, as the aging society rapidly develops, the number ofpatients with senile diseases, particularly, the number of patients withbone diseases has been steadily increasing. Among them, osteoporosis isa serious problem, which often occurs in women, particularly,postmenopausal women. The accelerated bone resorption caused by thehormone imbalance or the aging process in postmenopausal women isclosely involved in the development and progression of bone diseases.Therefore, bone resorption inhibitors are generally used in drug therapyfor osteoporosis. However, bone resorption-inhibiting drugs being usedcurrently, such as calcitonin preparations, estrogen preparations,vitamin K preparations, and bisphosphonate preparations, have problemswith their therapeutic efficacy, immediate effectivity, side effects,dose compliance, or the like, and there has been a demand for thedevelopment of bone resorption inhibitors having the potential to becomemore effective drugs for treating or preventing osteoporosis.

In the living body, equilibrium is maintained between the concentrationsof calcium in the bone and in the blood, and calcium constantly movesbetween the bone and the blood. Such movement of calcium between thebone and the blood is managed by the dynamic turnover between boneformation and bone resorption. It is known that in the bone resorptionprocess, activated osteoclasts dissolve bone minerals such as calciumwhile the cysteine proteases released from the osteoclasts decompose theorganic components of the bone, such as collagen, so that boneresorption is accelerated. Cysteine proteases such as cathepsins B, H,L, and S are present in the lysosomes of osteoclasts. In 1995, humancathepsin K localized in osteoclasts was isolated and found to beproduced more in osteoclasts than other cathepsins (see Non PatentLiteratures 1 and 2). It was also found that dwarfism patients withabnormal bone resorption have a mutation of the cathepsin K gene (seeNon Patent Literature 3).

Thus, cathepsin K has attracted attention as the principal cysteineprotease involved in bone resorption, and cathepsin K inhibitors areincreasingly expected as bone resorption inhibitors. Aldehydederivatives, epoxysuccinic acid derivatives (see Non Patent Literatures4 and 5), or vinylsulfonic acid derivatives (see Non Patent Literatures6 and 7) have been previously reported as cathepsin K-inhibitingcompounds. Unfortunately, these derivatives are known to have lowselectivity and to inhibit not only cathepsin K but also other cysteineproteases strongly (see Non Patent Literatures 8 to 10).

As cathepsin K has attracted attention as mentioned above, studies suchas X-ray crystallography of cathepsin K and inhibitors have beenactively conducted (see Non Patent Literatures 6 and 11), and somecompounds are currently known to have the effect of selectivelyinhibiting cathepsin K (see Patent Literatures 1 to 4 and Non PatentLiteratures 12 to 15).

Cytochrome P450 (hereinafter also referred to as CYP) is a typicalenzyme involved in drug metabolism. In particular, CYP3A4 is a molecularspecies involved in the metabolism of at least 50% of the drugs beingclinically used at present. The presence of a drug capable of inhibitinga drug metabolism enzyme may incur the risk of causing or enhancing sideeffects by preventing the enzyme from metabolizing another drug used incombination and increasing the blood concentration of the drug used incombination (see Non Patent Literatures 16 and 17). At present,therefore, checking for CYP3A4 inhibitory activity is generallyperformed at the initial stage of drug development studies, andinhibitory compounds are generally excluded from candidate compounds(see Non Patent Literature 17). In particular, it is considered thatdrugs for treating osteoporosis must have low CYP3A4 inhibitory activitybecause elderly people, who are to be given the drugs, often take acombination of drugs and often have decreased drug metabolism.

IC₅₀ values (50% inhibitory concentrations) are generally used todetermine the intensity of the CYP inhibitory activity. In general, theintensity is classified as a high level when IC₅₀<1 μM, a medium levelwhen 1 μM<IC₅₀<10 μM, and a low level when IC₅₀>10 μM (see Non PatentLiteratures 18 and 19). Therefore, compounds with an IC₅₀ of more than10 μM as the intensity of CYP3A4 inhibitory activity must be selectedfor drugs for chronic diseases of elderly people.

CITATION LIST Patent Literatures

-   Patent Literature 1: JP 2000-204071 A-   Patent Literature 2: WO 98/01133-   Patent Literature 3: WO 01/58886-   Patent Literature 4: WO 03/075836

Non Patent Literatures

-   Non Patent Literature 1: Biochem. Biophys. Res. Commun., 206, p 89    (1995)-   Non Patent Literature 2: J. Biol. Chem., 271, p 12511 (1996)-   Non Patent Literature 3: Science, 273, p 1236 (1996)-   Non Patent Literature 4: J. Biol. Chem., 271, p 2126 (1996)-   Non Patent Literature 5: Biol. Pharm. Bull., 19, p 1026 (1996)-   Non Patent Literature 6: Nature Structural Biology, 4, p 105 (1997)-   Non Patent Literature 7: J. Med. Chem., 38, p 3193 (1995)-   Non Patent Literature 8: Enzyme Inhibition, 3, p 13 (1989)-   Non Patent Literature 9: Biochem. Biophys. Res. Commun., 153, p 1201    (1988)-   Non Patent Literature 10: J. Biochem., 88, p 1805 (1980)-   Non Patent Literature 11: Nature Structural Biology, 4, p 109 (1997)-   Non Patent Literature 12: Proc. Natl. Acad. Sci. USA., 94, p 14249    (1997)-   Non Patent Literature 13: J. Am. Chem. Soc., 120, p 9114 (1998)-   Non Patent Literature 14: J. Med. Chem., 41, p 3563 (1998)-   Non Patent Literature 15: Bioorg. Med. Chem. Lett., 14, p 4897    (2004)-   Non Patent Literature 16: Rinsho Yakubutsu Dotaigaku (Clinical    Pharmacokinetics) (revised 4th edition), Nankodo Co., Ltd., p 71-85,    p 173-228 (2009)-   Non Patent Literature 17: Nichiyakurishi (Folia Pharmacol. Jpn.),    134, p 285-288 (2009)-   Non Patent Literature 18: Phytomedicine. 2011 Apr. 15; 18(6): p    533-8-   Non Patent Literature 19: Annu. Rev. Pharmacol. Toxicol. 2000; 40: p    133-57

SUMMARY OF INVENTION Technical Problem

The present invention provides a novel compound that has cathepsin Kinhibitory activity but has substantially no CYP3A4 inhibitory activity.More specifically, the present invention provides a bone resorptioninhibitor having substantially no CYP3A4 inhibitory activity and apharmaceutical composition useful for preventing and/or treatingdiseases caused by accelerated bone resorption, such as osteoporosis.

More specifically, the present invention provides a novel compound thathas extremely low CYP3A4 inhibitory activity and is highly effective notonly in inhibiting cathepsin K in vitro but also in inhibiting boneresorption in vivo; a bone resorption inhibitor including such a novelcompound; and a pharmaceutical composition useful for preventing and/ortreating diseases caused by accelerated bone resorption, such asosteoporosis.

Solution to Problem

So far, the inventors have developed a large number of cathepsinK-inhibiting compounds and tried to put them into practical use as drugsfor treating metabolic bone diseases. Unfortunately, these compoundshave been found to have high CYP3A4 inhibitory activity and have notbeen put into practical use yet. Thus, the inventors have activelysearched for compounds that have cathepsin K inhibitory activity buthave no CYP3A4 inhibitory activity. As a result, the inventors havesurprisingly found that α-oxoacylaminocaprolactam derivatives, morespecifically, compounds of formula (I) shown below exhibit almost noCYP3A4 inhibition and have high cathepsin K inhibitory activity, andhave accomplished the present invention based on these findings.

Specifically, the present invention is directed to a novelα-oxoacylaminocaprolactam derivative and a pharmaceutical composition,specifically a bone resorption inhibitor, including the derivative as anactive ingredient.

More specifically, the present invention is directed to items [1] to[14] below.

-   [1] An α-oxoacylaminocaprolactam derivative of formula (I):

wherein X is —O— or —N(R¹)—, wherein R¹ is a (C1 to C10 alkoxy)carbonylgroup.

-   [2] The α-oxoacylaminocaprolactam derivative according to item [1],    wherein in formula (I), X is —O—.-   [3] The α-oxoacylaminocaprolactam derivative according to item [1],    wherein in formula (I), X is —N(R¹)—, wherein R¹ is a (C1 to C10    alkoxy)carbonyl group.-   [4] The α-oxoacylaminocaprolactam derivative according to item [3],    wherein R¹ is a methoxycarbonyl group.-   [5] A bone resorption inhibitor including the    α-oxoacylaminocaprolactam derivative according to any one of items    [1] to [4].-   [6] A pharmaceutical composition including the    α-oxoacylaminocaprolactam derivative according to any one of items    [1] to [4] and a pharmaceutically acceptable carrier.-   [7] The pharmaceutical composition according to item [6], which is a    medicament for treating or preventing a disease caused by    accelerated bone resorption.-   [8] The pharmaceutical composition according to item [7], wherein    the disease caused by accelerated bone resorption is osteoporosis,    hypercalcemia, Paget's disease, bone resorption disease,    osteogenesis imperfecta, osteoarthritis, rheumatoid arthritis,    arthritis, Klinefelter syndrome, hereditary hyperphosphatasia,    Charcot neuroarthropathy, mastocytosis, Gaucher disease, cancer    metastasis, or multiple myeloma.-   [9] A method of treating a disease caused by accelerated bone    resorption, including administering an effective amount of the    α-oxoacylaminocaprolactam derivative according to any one of items    [1] to [4] to a patient with a disease caused by accelerated bone    resorption.-   [10] The method according to item [9], wherein the disease caused by    accelerated bone resorption is osteoporosis, hypercalcemia, Paget's    disease, bone resorption disease, osteogenesis imperfecta,    osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter    syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy,    mastocytosis, Gaucher disease, cancer metastasis, or multiple    myeloma.-   [11] The α-oxoacylaminocaprolactam derivative according to any one    of items [1] to [4], which is for use in a method of treating or    preventing a disease caused by accelerated bone resorption.-   [12] The α-oxoacylaminocaprolactam derivative according to item    [11], wherein the disease caused by accelerated bone resorption is    osteoporosis, hypercalcemia, Paget's disease, bone resorption    disease, osteogenesis imperfecta, osteoarthritis, rheumatoid    arthritis, arthritis, Klinefelter syndrome, hereditary    hyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucher    disease, cancer metastasis, or multiple myeloma.-   [13] Use of the α-oxoacylaminocaprolactam derivative according any    one of items [1] to [4] for the manufacture of a pharmaceutical    composition for treating or preventing a disease caused by    accelerated bone resorption.-   [14] The use according to item [13], wherein the disease caused by    accelerated bone resorption is osteoporosis, hypercalcemia, Paget's    disease, bone resorption disease, osteogenesis imperfecta,    osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter    syndrome, hereditary hyperphosphatasia, Charcot neuroarthropathy,    mastocytosis, Gaucher disease, cancer metastasis, or multiple    myeloma.

Advantageous Effects of Invention

The α-oxoacylaminocaprolactam derivative of formula (I) of the presentinvention, which has high cathepsin K inhibitory activity with only alow level of CYP3A4 inhibitory activity, can be used as an activeingredient in a pharmaceutical composition for preventing and/ortreating diseases that can be ameliorated by inhibiting substantial boneresorption (such as osteoporosis, hypercalcemia, Paget's disease, boneresorption disease, osteogenesis imperfecta, osteoarthritis, rheumatoidarthritis, arthritis, Klinefelter syndrome, hereditaryhyperphosphatasia, Charcot neuroarthropathy, mastocytosis, Gaucherdisease, cancer metastasis, and multiple myeloma). The compound of thepresent invention has not only cathepsin K inhibitory activity in vitrobut also high bone resorption inhibitory activity in vivo.

The α-oxoacylaminocaprolactam derivative of formula (I) of the presentinvention, which only has a low level of CYP3A4 inhibitory activity, isless likely to cause serious side-effects even when used in combinationwith other drugs. Therefore, the α-oxoacylaminocaprolactam derivative offormula (I) of the present invention can be safely administered toelderly people who suffer from different diseases and take many drugs incombination.

Therefore, the present invention provides a pharmaceutical compositionfor preventing and/or treating diseases caused by accelerated boneresorption, which includes, as an active ingredient, a safe, practical,orally-administrable compound that has bone resorption inhibitoryactivity and is less likely to cause serious side-effects even when usedin combination with other drugs.

DESCRIPTION OF EMBODIMENTS

The α-oxoacylaminocaprolactam derivative of the present invention is acompound of formula (I) shown above. In each molecule of the compound offormula (I) of the present invention, any of the hydrogen atoms may bereplaced by deuterium or tritium atoms.

The α-oxoacylaminocaprolactam derivative of formula (I) of the presentinvention is characterized in that it has a caprolactam (ε-lactam) groupat the end, a nitrogen atom is bonded in the α-position relative to thecaprolactam group, the steric configuration at the α-position is the Sconfiguration, it has an isopropyl group at the center, the stericconfiguration of the carbon atom bonded to the isopropyl group is the Sconfiguration, and it has a 1-amino-cyclohexanecarboxylic acidstructure. The α-oxoacylaminocaprolactam derivative of formula (I) ofthe present invention is further characterized by having a saturatedoxygen atom or a nitrogen atom-containing heterocyclic group,specifically, a tetrahydro-2H-pyran-4-yl group or a1-(alkoxycarbonyl)-4-piperidinyl group, at the end.

The α-oxoacylaminocaprolactam derivative of the present invention isfurther characterized in that it has almost no CYP3A4 inhibitoryactivity but has high cathepsin K inhibitory activity, which is itsspecific property.

The α-oxoacylaminocaprolactam derivative of the present invention andthe compound described in Patent Literature 1 are different compoundsbecause the α-oxoacylaminocaprolactam derivative of the presentinvention differs in the R¹ moiety of the compound described in PatentLiterature 1. Specifically, Patent Literature 1 states that R¹ may be asubstituted amide group, and also states that the substituted amidegroup refers to a group represented by the formula R⁹—CONH— and havingany of various substituents on the carbon atom of the amide bond group,in which the substituent R⁹ on the carbon atom may be the substituted orunsubstituted alkyl group, substituted alkoxy, phenoxy, 1-naphthyloxy,2-naphthyloxy, substituted or unsubstituted alkenyl, substituted orunsubstituted amino, substituted or unsubstituted aromatic hydrocarbon,or substituted or unsubstituted heterocycle (Patent Literature 1, claim6). In contrast, the α-oxoacylaminocaprolactam derivative of the presentinvention has a heterocycle-substituted oxy group (heterocyclyloxygroup) in place of the R⁹ substituent shown in Patent Literature 1. Thecompound of the present invention differs in this point from thecompound described in Patent Literature 1.

In the α-oxoacylaminocaprolactam derivative of formula (I) of thepresent invention, the (C1 to C10 alkoxy)carbonyl group for R¹ is agroup composed of an alkyl group and an oxycarbonyl group (—O—CO— group)bonded to the alkyl group, in which the alkyl group has 1 to 10 carbonatoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbonatoms. In the alkoxycarbonyl group, the total number of carbon atomsincluding the carbon atom of the carbonyl group is 2 to 11, preferably 2to 7, more preferably 2 to 5. The (C1 to C10 alkoxy)carbonyl group maybe, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl,isopropoxycarbonyl, tert-butoxycarbonyl, or the like. The alkoxycarbonylgroup is more preferably methoxycarbonyl.

The α-oxoacylaminocaprolactam derivative of formula (I) of the presentinvention may be the following:

[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]carbamicacid tetrahydro-2H-pyran-4-yl ester;

[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]carbamicacid 1-(methoxycarbonyl)-4-piperidinyl ester; or the like.

The α-oxoacylaminocaprolactam derivative of formula (I) of the inventionencompasses not only an α-oxoacylaminocaprolactam derivative of formula(I) but also a pharmaceutically acceptable salt thereof, any of varioushydrates and solvates thereof, any of crystal polymorphisms thereof, adeuterated derivative thereof, a tritiated derivative thereof, or thelike. When the oxygen atom- or nitrogen atom-containing heterocyclicmoiety in formula (I) further has an asymmetric center atom, theα-oxoacylaminocaprolactam derivative of formula (I) also encompasses anystereoisomer thereof or a mixture of stereoisomers thereof.

Solvates of the α-oxoacylaminocaprolactam derivative of formula (I)include hydrates and various solvates (e.g., solvates with water or analcohol such as ethanol).

The α-oxoacylaminocaprolactam derivative of formula (I) of the presentinvention can be produced by an appropriate combination of knownchemical synthesis techniques. For example, theα-oxoacylaminocaprolactam derivative of formula (I) can be produced bythe method shown below or a method similar thereto.

In the formulae, R is an ester residue, Boc is a tert-butoxycarbonylgroup, and X is the same as defined above.

First Process

This process includes producing an isocyanate of formula (III) from anaminocyclohexanecarboxylic acid ester derivative of formula (II) andthen allowing the isocyanate of formula (III) to react with an alcoholto produce an oxyamidocyclohexanecarboxylic acid ester derivative offormula (IV).

The process of producing the isocyanate (III) from theaminocyclohexanecarboxylic acid ester derivative of formula (II) may beperformed by a technique using di-tert-butyl dicarbonate and4-(dimethylamino)pyridine or a technique using phosgene or triphosgene.In this process, if necessary, a base may be added, such as pyridine,triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine,N-methylmorpholine, or N,N-dicyclohexylamine. This process is preferablyperformed in a solvent such as dichloromethane, chloroform,dichloroethane, ethyl acetate, acetone, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, diethylether, diisopropyl ether, or dimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200°C., preferably in the range of 0° to 100° C.

The process of producing the oxyamidocyclohexanecarboxylic acid esterderivative of formula (IV) by reaction of the isocyanate of formula(III) with an alcohol may be performed without any solvent or in asolvent. The solvent may be, for example, chloroform, dichloroethane,ethyl acetate, benzene, toluene, xylene, chlorobenzene, dichlorobenzene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, or the like.In this process, a base may also be added, such as pyridine,triethylamine, N,N-diisopropylethylamine, 4-(dimethylamino)pyridine,N-methylmorpholine, or N,N-dicyclohexylamine. The base may be added inan amount in the range of a catalytic amount to an excess amount.

The reaction temperature may be in the range of 0° C. to 300° C.,preferably in the range of 40° to 150° C.

The aminocyclohexanecarboxylic acid ester derivative of formula (II) maybe a C1 to C6 linear or branched alkyl ester, preferably a C1 to C4linear or branched alkyl ester; a C7 to C15 arylalkyl ester, preferablya C7 to C12 arylalkyl ester, or the like. Examples include1-aminocyclohexanecarboxylic acid methyl ester,1-aminocyclohexanecarboxylic acid ethyl ester,1-aminocyclohexanecarboxylic acid n-propyl ester,1-aminocyclohexanecarboxylic acid 2-propyl ester,1-aminocyclohexanecarboxylic acid n-butyl ester,1-aminocyclohexanecarboxylic acid 2-methylpropyl ester,1-aminocyclohexanecarboxylic acid 1,1-dimethylethyl ester,1-aminocyclohexanecarboxylic acid benzyl ester, and the like.

The alcohol to be allowed to react with the isocyanate of formula (III)may be, for example, tetrahydro-4-pyranol,1-(alkoxycarbonyl)-4-hydroxypiperidine, preferably1-tert-butoxycarbonyl-4-hydroxypiperidine,1-methoxycarbonyl-4-hydroxypiperidine, or the like.

The oxyamidocyclohexanecarboxylic acid ester derivative of formula (IV)may be, for example,

1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid methyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid n-propyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid 2-propyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid n-butyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid 2-methylpropyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid 1,1-dimethylethyl ester,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester;

1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid methyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid n-propyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid 2-propyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid n-butyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid 2-methylpropyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid 1,1-dimethylethyl ester,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester;

1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid methyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid ethyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid n-propyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid 2-propyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid n-butyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid 2-methylpropyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid 1,1-dimethylethyl ester,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester; or the like.

Second Process

This process includes subjecting the oxyamidocyclohexanecarboxylic acidester derivative of formula (IV) (produced in the first process) to ahydrolysis reaction or a hydrogenation reaction using a metal catalystfor catalytic reduction to produce an oxyamidocyclohexanecarboxylic acidof formula (V).

The hydrolysis reaction may be performed in the presence of an acid or abase. The acid may be, for example, hydrochloric acid, sulfuric acid,nitric acid, acetic acid, methanesulfonic acid, benzenesulfonic acid,p-toluenesulfonic acid, or the like. The base may be, for example,sodium hydroxide, potassium hydroxide, lithium hydroxide, sodiumcarbonate, potassium carbonate, or the like. This process is preferablyperformed in water or a mixed solvent of water and an organic solventsuch as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol,tetrahydrofuran, or dimethoxyethane. The reaction temperature isgenerally in the range of −20° C. to 200° C., preferably in the range of0° to 180° C.

When the oxyamidocyclohexanecarboxylic acid ester derivative of formula(IV) is a benzyl ester (R is benzyl), the oxyamidocyclohexanecarboxylicacid of formula (V) can be produced by a hydrogenation reaction using ametal catalyst for catalytic reduction. The metal catalyst for theproduction by the catalytic hydrogenation reaction may be, for example,a platinum catalyst such as PtO₂ or Pt/C, a palladium catalyst such asPd/C, Pd/BaSO₄, Pd/CaCO₃, Pd/SrCO₃, Pd black, PdO, or Pd(OH)₂, a nickelcatalyst such as Raney nickel, a rhodium catalyst such as Rh/C,Rh/Al₂O₃, RhCl(PPh₃)₃, RhH(CO)(PPh₃)₃, or Rh(OCOCH₃)₄, a rutheniumcatalyst such as RuO₂, Ru/C, Ru(OCOMe)(PPh₃)₃, or Ru(OCOCF₃)(PPh₃)₃, acopper catalyst such as Cu—CrO, Cu—Ba—CrO, or the like.

This process is preferably performed in a solvent such as methanol,ethanol, 2-propanol, 1-butanol, 2-butanol, isobutanol, diisopropylether, tetrahydrofuran, benzene, toluene, xylene, dimethylformamide,dioxane, or water. The reaction temperature is generally in the range of−50° C. to 200° C., preferably in the range of 10° to 100° C.

The oxyamidocyclohexanecarboxylic acid derivative of formula (V) may be,for example,1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid,1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid,1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid, or the like.

Third Process

This process includes oxidizing tert-butoxycarbonyl-L-valinol of formula(VI) to produce tert-butoxycarbonyl-L-valinal of formula (VII).

In this process, the oxidation reaction may be activated DMSO (dimethylsulfoxide) oxidation. In this reaction, an electrophilic activatingreagent may be used, such as dicyclohexylcarbodiimide, phosphoruspentoxide, a pyridine-sulfur trioxide complex, acetic anhydride,mercury(II) acetate, or oxalyl chloride. In this process, if necessary,a hydrogen donor may also be added, such as phosphoric acid,trifluoroacetic acid, dichloroacetic acid, pyridine-phosphoric acid, orpyridine-trifluoroacetic acid. If necessary, an amine may also be added,such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine.

This process may be performed in dimethyl sulfoxide, and if necessary, asolvent may also be added, such as dichloromethane, chloroform,dichloroethane, toluene, acetone, or tetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200°C., preferably in the range of −40° to 40° C.

Alternatively, in this process, an active species with a structuresimilar to that for the activated DMSO reaction may be prepared from asulfide and a halogen for the oxidation reaction.

In this process, the sulfide may be, for example, dimethyl sulfide,methyl phenyl sulfide, or the like. The halogenating agent may be, forexample, N-chlorosuccinimide, chlorine, or the like.

In this process, if necessary, an amine may also be added, such astriethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or1,8-diazabicyclo[5.4.0]undec-7-en (DBU).

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, toluene, ortetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200°C., preferably in the range of −40° to 40° C.

Alternatively, in this process, the oxidation may be performed using ahigh-valence iodine compound reagent.

In this process, the high-valence iodine compound may be, for example, aDess-Martin reagent(1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one), IBX(1-hydroxy-1,2-benziodoxol-3-(1H)-1-oxide), or the like.

In this process, if necessary, a base may also be added, such aspyridine or sodium hydrogen carbonate.

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, ordimethoxyethane.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 40° C.

Alternatively, in this process, the oxidation may be performed using analuminum alkoxide and a hydrogen acceptor (Oppenauer oxidation). Thealuminum alkoxide may be, for example, aluminum isopropoxide or aluminumtert-butoxide.

The hydrogen acceptor may be, for example, benzoquinone, benzophenone,acetone, cyclohexanone, benzaldehyde, or the like.

This process is preferably performed in a solvent such as benzene,toluene, or xylene.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 150° C.

Alternatively, in this process, the oxidation reaction may be performedusing tetrapropylammonium perruthenate (TPAP).N-methylmorpholine-N-oxide or molecular oxygen may be used as anoxidizing agent.

This process is preferably performed in a solvent such asdichloromethane, acetonitrile, or toluene. In this process, ifnecessary, molecular sieves 4A may be added.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 40° C.

Alternatively, in this process, the oxidation reaction may be performedusing 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or aderivative thereof.

A hypochlorite is preferably used as an oxidizing agent. A bromite,N-chlorosuccinimide, or the like may also be used as an oxidizing agent.

This process is preferably performed in a solvent such as dimethylsulfoxide, dimethylformamide, dichloromethane, acetonitrile, toluene, orethyl acetate.

In this process, if necessary, sodium bromide or water may also beadded.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 40° C.

Fourth Process

This process includes adding a cyano group to thetert-butoxycarbonyl-L-valinal of formula (VII) to produce a cyanohydrinof formula (VIII), then subjecting the cyanohydrin of formula (VIII) toa hydrolysis reaction, and performing tert-butoxycarbonylation again toproduce a hydroxycarboxylic acid of formula (IX).

In this process, the reaction to produce the cyanohydrin of formula(VIII) from the tert-butoxycarbonyl-L-valinal of formula (VII) may beperformed using acetone cyanhydrin, sodium cyanide, potassium cyanide,hydrogen cyanide, copper cyanide, trimethylsilyl cyanide, or the like.If necessary, a base may also be added, such as pyridine, triethylamine,N,N-diisopropylethylamine, 4-(dimethylamino)pyridine,N-methylmorpholine, or N,N-dicyclohexylamine, or a Lewis acid may alsobe added, such as zinc chloride, titanium tetrachloride, titaniumtetraisopropoxide, aluminum chloride, or zinc trifluoromethanesulfonate.

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, ethyl acetate, benzene,toluene, xylene, chlorobenzene, dichlorobenzene, dimethylformamide,acetonitrile, tetrahydrofuran, or dioxane.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 100° C.

In this process, the cyanohydrin of formula (VIII) may be subjected toan acid hydrolysis reaction using an acid such as hydrochloric acid,sulfuric acid, nitric acid, acetic acid, methanesulfonic acid,benzenesulfonic acid, or p-toluenesulfonic acid. This reaction ispreferably performed in water or a mixed solvent of water and an organicsolvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol,isobutanol, tetrahydrofuran, dioxane, or dimethoxyethane. The reactiontemperature is generally in the range of −20° C. to 200° C., preferablyin the range of 0° to 180° C.

In the acid hydrolysis reaction, the Boc group for the amino group canalso be decomposed simultaneously. To protect the amino group,therefore, tert-butoxycarbonylation reaction is preferably performed.

In this process, the tert-butoxycarbonylation reaction may be performedagain using di-tert-butyl dicarbonate,2-(tert-butoxycarbonylthio)-4,6-dimethylpyrimidine, or the like. Thereaction may be performed in the presence of a base. The base may be anorganic base such as pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, or N,N-dicyclohexylamine,or an inorganic base such as sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium hydrogen carbonate, sodium carbonate, orpotassium carbonate. This process is preferably performed in water or amixed solvent of water and an organic solvent such as methanol, ethanol,2-propanol, 1-butanol, 2-butanol, isobutanol, tetrahydrofuran, dioxane,ethyl acetate, diethyl ether, diisopropyl ether, or dimethoxyethane. Thereaction temperature is generally in the range of −20° C. to 200° C.,preferably in the range of −10° to 100° C.

Fifth Process

This process includes condensing the hydroxycarboxylic acid of formula(IX) with L-(−)-α-amino-ε-caprolactam, preferably in the presence of acondensing agent, and then deprotecting the product to produce anaminoalcohol of formula (X).

The condensing agent for use in this process may be, for example,dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, diisopropylcarbodiimide, carbonyldiimidazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM), 2-chloro-1-methylpyridinium iodide, or the like. Inthis process, if necessary, an activating agent may also be added, suchas 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Alternatively, in this process, the condensation may be performed by amixed acid anhydride method using an acid halide in the presence of abase. The acid halide for use in this process may be, for example,pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethylchloroformate, methanesulfonyl chloride, benzenesulfonyl chloride,toluenesulfonyl chloride, or the like. The base may be, for example,pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, N,N-dicyclohexylamine, orthe like.

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, ethyl acetate, acetone,benzene, toluene, xylene, dimethylformamide, acetonitrile,tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, ordimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200°C., preferably in the range of −10° to 100° C.

The subsequent deprotection reaction may be performed using an acid suchas hydrogen chloride, hydrochloric acid, sulfuric acid, nitric acid,acetic acid, methanesulfonic acid, benzenesulfonic acid, orp-toluenesulfonic acid. This reaction is preferably performed in asolvent such as methanol, ethanol, 2-propanol, 1-butanol, 2-butanol,isobutanol, tetrahydrofuran, dioxane, ethyl acetate, or dimethoxyethane.

Sixth Process

This process includes condensing the oxyamidocyclohexanecarboxylic acidof formula (V) with the aminoalcohol of formula (X), preferably in thepresence of a condensing agent, to produce anα-hydroxyacylaminocaprolactam of formula (XI).

The condensing agent for use in this process may be, for example,dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, diisopropylcarbodiimide, carbonyldiimidazole,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloriden-hydrate (DMT-MM), 2-chloro-1-methylpyridinium iodide, or the like. Inthis process, if necessary, an activating agent may also be added, suchas 1-hydroxybenzotriazole or N-hydroxysuccinimide.

Alternatively, in this process, the condensation may be performed by amixed acid anhydride method using an acid halide in the presence of abase. The acid halide for use in this process may be, for example,pivaloyl chloride, isobutyl chloroformate, methyl chloroformate, ethylchloroformate, methanesulfonyl chloride, benzenesulfonyl chloride,toluenesulfonyl chloride, or the like. The base may be, for example,pyridine, triethylamine, N,N-diisopropylethylamine,4-(dimethylamino)pyridine, N-methylmorpholine, N,N-dicyclohexylamine, orthe like.

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, ethyl acetate, acetone,benzene, toluene, xylene, dimethylformamide, acetonitrile,tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, ordimethoxyethane.

The reaction temperature is generally in the range of −30° C. to 200°C., preferably in the range of −10° to 100° C.

Seventh Process

This process includes oxidizing the α-hydroxyacylaminocaprolactam offormula (XI) to produce the α-oxyacylaminocaprolactam of formula (I).

In this process, the oxidation reaction may be activated DMSO (dimethylsulfoxide) oxidation. In this reaction, an electrophilic activatingreagent may be used, such as dicyclohexylcarbodiimide, phosphoruspentoxide, a pyridine-sulfur trioxide complex, acetic anhydride,mercury(II) acetate, or oxalyl chloride. In this process, if necessary,a hydrogen donor may also be added, such as phosphoric acid,trifluoroacetic acid, dichloroacetic acid, pyridine-phosphoric acid, orpyridine-trifluoroacetic acid. If necessary, an amine may also be added,such as triethylamine, N,N-diisopropylethylamine, or N-methylmorpholine.

This process may be performed in dimethyl sulfoxide, and if necessary, asolvent may be added, such as dichloromethane, chloroform,dichloroethane, toluene, acetone, or tetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200°C., preferably in the range of −40° to 40° C.

Alternatively, in this process, an active species with a structuresimilar to that for the activated DMSO reaction may be prepared from asulfide and a halogen for the oxidation reaction.

In this process, the sulfide may be, for example, dimethyl sulfide,methyl phenyl sulfide, or the like. The halogenating agent may be, forexample, N-chlorosuccinimide, chlorine, or the like.

In this process, if necessary, an amine may also be added, such astriethylamine, N,N-diisopropylethylamine, N-methylmorpholine, or1,8-diazabicyclo[5.4.0]undec-7-en (DBU).

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, toluene, ortetrahydrofuran.

The reaction temperature is generally in the range of −80° C. to 200°C., preferably in the range of −40° to 40° C.

Alternatively, in this process, the oxidation may be performed using ahigh-valence iodine compound reagent.

In this process, the high-valence iodine compound may be, for example, aDess-Martin reagent(1,1,1-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one), IBX(1-hydroxy-1,2-benziodoxol-3-(1H)-1-oxide), or the like.

In this process, if necessary, a base may also be added, such aspyridine or sodium hydrogen carbonate.

This process is preferably performed in a solvent such asdichloromethane, chloroform, dichloroethane, benzene, toluene, xylene,dimethylformamide, acetonitrile, tetrahydrofuran, dioxane, ordimethoxyethane.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 40° C.

Alternatively, in this process, the oxidation may be performed using analuminum alkoxide and a hydrogen acceptor (Oppenauer oxidation). Thealuminum alkoxide may be, for example, aluminum isopropoxide or aluminumtert-butoxide.

The hydrogen acceptor may be, for example, benzoquinone, benzophenone,acetone, cyclohexanone, benzaldehyde, or the like.

This process is preferably performed in a solvent such as benzene,toluene, or xylene.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 150° C.

Alternatively, in this process, the oxidation reaction may be performedusing tetrapropylammonium perruthenate (TPAP).N-methylmorpholine-N-oxide or molecular oxygen may be used as anoxidizing agent.

This process is preferably performed in a solvent such asdichloromethane, acetonitrile, or toluene. In this process, ifnecessary, molecular sieves 4A may be added.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 40° C.

Alternatively, in this process, the oxidation reaction may be performedusing 2,2,6,6-tetramethyl-1-piperidinyloxy radical (TEMPO) or aderivative thereof.

A hypochlorite is preferably used as an oxidizing agent. A bromite,N-chlorosuccinimide, or the like may also be used as an oxidizing agent.

This process is preferably performed in a solvent such as dimethylsulfoxide, dimethylformamide, dichloromethane, acetonitrile, toluene, orethyl acetate. In this process, if necessary, sodium bromide or watermay also be added.

The reaction temperature may be in the range of −20° C. to 200° C.,preferably in the range of 0° to 40° C.

If necessary, the intermediates and the α-oxoacylaminocaprolactamderivative of formula (I) of the present invention, produced by any ofthese processes, may be purified by any of various known purificationmethods such as recrystallization, distillation, and chromatography. Ifnecessary, optical resolution may also be performed by any of variousknown methods.

The test results described below show that in the evaluation ofcathepsin K inhibitory activity and the evaluation of bone resorptioninhibitory activity using male mice, the α-oxoacylaminocaprolactamderivative of formula (I) of the present invention has activity equal toor greater than that of the compounds (cyclic amides) in the groupdescribed in JP 2000-204071 A, which are known to have cathepsin Kinhibitory activity. However, the compounds (cyclic amides) in the groupdescribed in JP 2000-204071 A have CYP3A4 inhibitory activity and cannotonly have bone resorption inhibitory activity without CYP3A4 inhibitoryactivity.

In contrast, compounds according to the present invention all have boneresorption inhibitory activity with no CYP3A4 inhibitory activity, whichmeans that the compound group of the present invention can only have thedesired pharmacological activity without any CYP3A4 inhibitory activitywhich may cause side effects.

Although it is not clear why the compound of the present invention hasbone resorption inhibitory activity with no CYP3A4 inhibitory activity,it is suggested that only compounds with an extremely limited structurecan be free of CYP3A4 inhibitory activity.

As shown below, the compound of the present invention has selective andpotent cathepsin K inhibitory activity and high bone resorptioninhibitory activity in an animal model. In addition, the compound of thepresent invention can serve as a bone resorption inhibitor with lessside effects even when used in combination with other drugs. Therefore,the compound of the present invention can be used as an activeingredient in pharmaceutical compositions for treating or preventingdiseases caused by accelerated bone resorption. Diseases caused byaccelerated bone resorption include osteoporosis, hypercalcemia, Paget'sdisease, bone resorption diseases, osteogenesis imperfecta,osteoarthritis, rheumatoid arthritis, arthritis, Klinefelter syndrome,hereditary hyperphosphatasia, Charcot neuroarthropathy, mastocytosis,Gaucher disease, cancer metastasis, multiple myeloma, and the like.

The bone resorption inhibitor of the present invention or thetherapeutic agent of the present invention for diseases caused byaccelerated bone resorption includes the α-oxoacylaminocaprolactamderivative of formula (I) as an active ingredient and can be used as apharmaceutical composition containing the active ingredient. In thiscase, the compound of the present invention is generally used togetherwith a pharmaceutically acceptable carrier and/or diluent, although thecompound of the present invention may be used alone.

The compound of the present invention may be administered by any method.A suitable preparation for the compound of the present invention may beselected as appropriate depending on the therapeutic purpose. Forexample, such a preparation may be any of an oral agent, an injection, asuppository, an inhalant, and the like. Pharmaceutical compositionssuitable for these dosage forms can be produced using known preparationmethods.

For example, when oral solid preparations are prepared, the compound offormula (I) may be mixed with a pharmaceutically acceptable excipientand optionally an additive such as a binder, a disintegrator, alubricant, a colorant, a corrigent, or a flavoring agent, and thentablets, coated tables, granules, powders, capsules, or the like may beprepared from the mixture using conventional methods. The additives maybe appropriately selected from those generally used in the art. Examplesof the excipient include lactose, sucrose, sodium chloride, glucose,starch, calcium carbonate, kaolin, microcrystalline cellulose, silicate,and the like. Examples of the binder include water, ethanol, propanol,simple syrup, glucose solutions, starch solutions, gelatin solutions,carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch,methyl cellulose, ethyl cellulose, shellac, calcium phosphate,polyvinylpyrrolidone, and the like. Examples of the disintegratorinclude dry starch, sodium alginate, agar powder, sodium hydrogencarbonate, calcium carbonate, sodium lauryl sulfate, stearic acidmonoglyceride, lactose, and the like. Examples of the lubricant includepurified talc, stearates, borax, polyethylene glycol, and the like.Examples of the corrigent include sucrose, bitter orange peel, citricacid, tartaric acid, and the like.

When an oral liquid preparation is prepared, internal liquid, syrup,elixir, or the like may be prepared by mixing the compound of formula(I) with a corrigent, a buffer, a stabilizer, a flavoring agent, and thelike using conventional methods. The corrigent may be any of thoselisted above. The buffer may be sodium citrate or the like, and thestabilizer may be gum tragacanth, gum arabic, gelatin, or the like.

When an injection is prepared, a hypodermic injection, an intramuscularinjection, and an intravenous injection may be prepared by mixing thecompound of formula (I) with a pH adjusting agent, a buffer, astabilizer, an isotonizing agent, a local anesthetic, and the like usingconventional methods. Example of the pH adjusting agent and the bufferinclude sodium citrate, sodium acetate, sodium phosphate, and the like.Examples of the stabilizer include sodium pyrosulfite, EDTA,thioglycolic acid, thiolactic acid, and the like. Examples of the localanesthetic include procaine hydrochloride, lidocaine hydrochloride, andthe like. Examples of the isotonizing agent include sodium chloride,glucose, and the like.

A suppository can be prepared by mixing the compound of formula (I) witha known suppository carrier, such as polyethylene glycol, lanolin, cacaobutter, or fatty acid triglyceride, and optionally a surfactant (such asTween (registered trademark)) and then forming the suppository usingconventional methods.

Besides those listed above, other preferred preparations may beappropriately prepared using conventional methods.

In general, 1 mg to 1,000 mg of the compound of formula (I) ispreferably administered to an adult orally or parenterally once or inseveral divided doses per day, although the dosage of the compound offormula (I) depends on the age, weight, and condition of the subject,dosage form, dosage frequency, and the like.

Hereinafter, the present invention will be more specifically describedwith reference to examples. It will be understood that the productionexamples and the examples are not intended to limit the presentinvention at all.

EXAMPLES Production Example 1 Production of1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid

(1) Production of1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester

Benzyl 1-aminocyclohexanecarboxylate (11.1 g, 50 mmol) was added to adichloromethane solution of di-tert-butyl dicarbonate (10.9 g, 50 mmol)and 4-dimethylaminopyridine (622 mg, 5 mmol) and stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated invacuo. Tetrahydro-4-pyranol (6.13 g, 60 mmol) andN,N-diisopropylethylamine (7.75 g, 60 mmol) were added to the residueand stirred at 100° C. for 12 hours. The reaction mixture was returnedto room temperature and diluted with 20% ethyl acetate/hexane. Thedilution was then washed once with a 10% potassium hydrogen sulfateaqueous solution and twice with water. After the organic layer was driedover anhydrous sodium sulfate, the solvent was removed by distillationin vacuo, so that 15.87 g (88%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ): 1.22-1.36 (1H, m), 1.40-1.68 (7H, m), 1.81-1.90 (4H,m), 1.95-2.09 (2H, m), 3.47 (2H, td, J=10 Hz, 3 Hz), 3.85 (2H, br-s),4.71-4.80 (1H, m), 4.87 (1H, br-s), 5.14 (2H, s), 7.26-7.36 (5H, m)

(2) Production of1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid

To a methanol solution of1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester (15.87 g, 43.9 mmol) was added 10% palladium-carbon(1.59 g) and stirred at room temperature under a hydrogen gas atmosphereovernight. The insoluble matter was removed by filtration, and thefiltrate was concentrated in vacuo. Diisopropyl ether was added to theresidue, and the resulting suspension was stirred overnight. Theresulting crystals were separated by filtration and dried in vacuo togive 10.83 g (91%) of the title compound.

¹H-NMR (CDCl₃, δ): 1.25-1.38 (1H, m), 1.39-1.52 (3H, m), 1.59-1.72 (4H,m), 1.80-2.11 (6H, m), 3.45-3.60 (2H, m), 3.90 (2H, br-s), 4.85 (1H,br-s), 4.92 (1H, br-s)

Production Example 2 Production of(2R,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamideand(2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide

(1) Production of Boc-L-valinal

Di-tert-butyl dicarbonate (211.6 g, 0.97 mol) was gradually added to adichloromethane solution of L-valinol (100.0 g, 0.97 mol). The reactionmixture was stirred at room temperature overnight and then concentratedin vacuo. To the residue (crude Boc-L-valinol) were addedN,N-diisopropylethylamine (51.7 g, 0.4 mol), 1 L of dry dimethylsulfoxide, and 200 ml of dry dichloromethane. Under ice cooling, sulfurtrioxide-pyridine (63.7 g, 0.4 mol) was gradually added to the liquidmixture and stirred at the same temperature for 1 hour. The reactionmixture was poured into ice-water and then extracted twice with ethylacetate. The organic layer was washed with a 20% citric acid aqueoussolution, a saturated sodium hydrogen carbonate aqueous solution, andbrine. After the organic layer was dried over anhydrous sodium sulfate,the solvent was removed by distillation in vacuo, so that 179.3 g (92%)of the title compounds were obtained.

¹H-NMR (CDCl₃, δ): 0.95 (3H, d, J=7 Hz), 1.04 (3H, d, J=7 Hz), 1.45 (9H,m), 2.24-2.34 (1H, m), 4.22-4.28 (1H, m), 5.08 (1H, br-s), 9.65 (1H, s)

(2) Production of(2RS,3S)-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoicacid

Under ice cooling, triethylamine (9.0 g, 89 mmol) was added dropwise toa dichloromethane solution of Boc-L-valinal (179.3 g, 881 mmol) andacetone cyanhydrin (310.6 g, 3.56 mol). The reaction mixture wasreturned to room temperature and then stirred overnight. The reactionmixture was concentrated in vacuo, and the residue was dissolved in 20%ethyl acetate/hexane. The solution was washed with water. The aqueouslayer was extracted with 20% ethyl acetate/hexane, and the extract wascombined with the organic layer. The organic layer was further washedwith water, and the aqueous layer was again extracted with 20% ethylacetate/hexane, and the extract was combined with the organic layer.After the combined organic layer was dried over anhydrous sodiumsulfate, the solvent was removed by distillation in vacuo. The residue(crude(2RS,3S)-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanenitrile)was dissolved in 500 ml of dioxane, and 500 ml of concentratedhydrochloric acid was added dropwise to the solution. The liquid mixturewas refluxed for 2 hours and then returned to room temperature. Thesolvent was then removed by distillation in vacuo. After the residue wasdissolved in water, 300 ml of triethylamine was added to the solution.The mixture was stirred at room temperature for 1 hour and thenconcentrated again in vacuo. The residue was dissolved in 400 ml ofdioxane and 400 ml of water. After triethylamine (108.3 g, 1.07 mol) wasadded to the solution, di-tert-butyl dicarbonate (194.2 g, 0.89 mol) wasadded to the mixture and then stirred at room temperature overnight. Thereaction mixture was concentrated. After the concentrate was dissolvedin diethyl ether, the solution was extracted once with water and twicewith 90 ml of a 1 M sodium hydroxide aqueous solution. Under icecooling, 15 ml of concentrated hydrochloric acid was added to thecombined aqueous layer. After returned to room temperature, the liquidmixture was acidified with potassium hydrogen sulfate and then extractedtwice with ethyl acetate. After the organic layer was dried overanhydrous sodium sulfate, the solvent was removed by distillation invacuo, so that 141.0 g (64%) of the title compound was obtained.

¹H-NMR (CDCl₃, δ): 0.99 (3H, d, J=7 Hz), 1.05 (3H, d, J=7 Hz), 1.42(9/2H, s), 1.45 (9/2H, s), 2.01-2.16 (1H, m), 3.55-3.68 (1H, m), 4.39(1/2H, d, J=2 Hz), 4.41 (1/2H, d, J=3 Hz), 4.86 (1/2H, d, J=7 Hz), 4.99(1/2H, d, J=10 Hz)

(3) Production of(2R,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamideand (4) production of(2S,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (120.2 g, 0.63 mol) was added to an N,N-dimethylformamidesolution of(2RS,3S)-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoicacid (141.0 g, 0.57 mol), L-(−)-α-amino-ε-caprolactam (73.1 g, 0.57mol), and 1-hydroxybenzotriazole (91.7 g, 0.60 mol). The reactionmixture was returned to room temperature, stirred overnight, and thenpoured into a 1:1 aqueous solution of a saturated sodium hydrogencarbonate aqueous solution and water. The precipitated crystals wereseparated by filtration and then washed with water. The filtrate wasextracted with chloroform, and the organic layer was washed with a 10%potassium hydrogen sulfate aqueous solution, saturated sodiumbicarbonate water, and brine, and then dried over sodium sulfate. Thesolvent was removed by distillation in vacuo. Ethyl acetate was added tothe residue and stirred for 4 hours. The precipitated crystals wereseparated by filtration and combined with the previously obtainedcrystals. The combined crystals were dissolved in methanol-chloroform.After the solution was dried over anhydrous sodium sulfate, the solventwas removed by distillation in vacuo, so that 105.2 g (52%) of titlecompound (3) was obtained. After the filtrate was concentrated in vacuo,diisopropyl ether was added to the residue and stirred overnight. Theprecipitated crystals were separated by filtration to give 76.9 g (38%)of title compound (4).

(3) ¹H-NMR (CDCl₃, δ): 0.98 (3H, d, J=7 Hz), 1.04 (3H, d, J=7 Hz),1.35-1.59 (2H, m), 1.38 (9H, s), 1.70-1.87 (2H, m), 1.92-2.16 (3H, m),3.20-3.33 (2H, m), 3.46 (1H, ddd, J=9 Hz, 9 Hz, 2 Hz), 4.33 (1H, d, J=2Hz), 4.52-4.61 (2H, m), 4.94 (1H, d, J=9 Hz), 6.25 (1H, br-s), 7.58 (1H,d, J=6 Hz)

(4) ¹H-NMR (CDCl₃, δ): 0.96 (3H, d, J=7 Hz), 1.02 (3H, d, J=7 Hz),1.32-1.59 (2H, m), 1.44 (9H, s), 1.77-1.91 (2H, m), 1.99-2.20 (2H, m),2.08-2.20 (1H, m), 3.21-3.34 (2H, m), 3.56 (1H, ddd, J=8 Hz, 8 Hz, 2Hz), 4.29 (1H, dd, J=6 Hz, 2 Hz), 4.52 (1H, dd, J=11 Hz, 6 Hz), 4.75(1H, d, J=6 Hz), 4.85 (1H, d, J=8 Hz), 6.06 (1H, br-s), 8.01 (1H, d, J=6Hz)

(5) Production of(2R,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide

Four M hydrochloric acid/dioxane was added to(2R,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide(105.2 g, 294 mmol) and allowed to stand at room temperature for 2hours. The reaction mixture was concentrated in vacuo. After the residuewas dissolved in water, the solution was allowed to pass through 180 mlof ion exchange resin (DOWEX, 1×4, 100-400 mesh). The eluate wasconcentrated in vacuo. The residue was dissolved in methanol-chloroform.After the solution was dried over anhydrous sodium sulfate, the solventwas removed by distillation in vacuo. Diisopropyl ether was added to theresidue and stirred overnight. The precipitated crystals were separatedby filtration to give 75.7 g (quantitative) of the title compound.

¹H-NMR (CDCl₃, δ): 1.01 (6H, d, J=7 Hz), 1.37-1.49 (1H, m), 1.56-1.68(1H, m), 1.74-1.94 (3H, m), 1.99-2.09 (2H, m), 3.05 (1H, dd, J=7 Hz, 2Hz), 3.22-3.37 (2H, m), 4.09 (1H, d, J=2 Hz), 4.57 (1H, dd, J=11 Hz, 7Hz), 6.29 (1H, br-s), 7.82 (1H, d, J=7 Hz)

(6) Production of(2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide

Using(2S,3S)—N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methyl-3-[[(1,1-dimethylethoxy)carbonyl]amino]pentanamide(76.9 g, 215 mmol), the same procedure as in the production (5) wasperformed to produce 40.8 g (74%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.88 (3H, d, J=7 Hz), 0.94 (3H, d, J=7 Hz), 1.32-1.47(1H, m), 1.52-1.60 (1H, m), 1.77-1.89 (2H, m), 1.98-2.08 (2H, m),2.14-2.32 (1H, m), 2.66 (1H, dd, J=9 Hz, 4 Hz), 3.29-3.35 (2H, m), 3.78(1H, d, J=9 Hz), 4.60 (1H, ddd, J=11 Hz, 6 Hz, 1 Hz), 5.97 (1H, br-s),9.32 (1H, d, J=6 Hz)

Production Example 3 Production of[1-[[[(1S,2R)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]carbamicacid tetrahydro-2H-pyran-4-yl ester

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (49.2 g, 257 mmol) was added to a dichloromethane solutionof1-[[[(tetrahydro-2H-pyran-4-yl)oxy]carbonyl]amino]cyclohexanecarboxylicacid (63.3 g, 233 mmol),(2R,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide(60.0 g, 233 mmol), 1-hydroxybenzotriazole (35.7 g, 245 mmol), andtriethylamine (28.3 g, 280 mmol). The liquid mixture was returned toroom temperature and stirred overnight. The reaction mixture was dilutedwith dichloromethane. The dilution was washed with a 10% potassiumhydrogen sulfate aqueous solution, a saturated sodium hydrogen carbonateaqueous solution, and brine. After the organic layer was dried overanhydrous sodium sulfate, the solvent was removed by distillation invacuo. Ethyl acetate was added to the residue and stirred overnight. Theprecipitated crystals were separated by filtration to give 107.4 g (90%)of the title compound.

¹H-NMR (CDCl₃, δ): 0.94 (3H, d, J=7 Hz), 1.03 (3H, d, J=7 Hz), 1.22-2.04(20H, m), 2.19-2.31 (1H, m), 3.19-3.33 (2H, m), 3.51 (2H, td, J=12 Hz, 3Hz), 3.62-3.69 (1H, m), 3.92 (2H, dt, J=12 Hz, 4 Hz), 4.31 (1H, dd, J=6Hz, 3 Hz), 4.52 (1H, dd, J=11 Hz, 7 Hz), 4.75-4.83 (1H, m), 4.93 (1H,s), 5.15 (1H, d, J=6 Hz), 6.10 (1H, br-s), 7.09 (1H, d, J=7 Hz), 7.71(1H, d, J=6 Hz)

Production Example 4 Production of[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]carbamicacid tetrahydro-2H-pyran-4-yl ester

Using(2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide(40.8 g, 159 mmol), the same procedure as in Production Example 3 wasperformed to produce 75.6 g (93%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.90 (3H, d, J=7 Hz), 1.00 (3H, d, J=7 Hz), 1.24-2.07(21H, m), 3.20-3.31 (2H, m), 3.45-3.54 (2H, m), 3.86-4.00 (3H, m), 4.23(1H, dd, J=9 Hz, 3 Hz), 4.49 (1H, dd, J=10 Hz, 6 Hz), 4.68 (1H, d, J=9Hz), 4.75-4.84 (1H, m), 5.10 (1H, s), 6.10 (1H, t, J=6 Hz), 7.20 (1H, d,J=8 Hz), 7.68 (1H, d, J=6 Hz)

Example 1 Production of[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]carbamicacid tetrahydro-2H-pyran-4-yl ester (compound 1)

Under ice cooling, sulfur trioxide-pyridine (43.8 g, 275 mmol) wasgradually added to a solution of[1-[[[(1S,2RS)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]carbamicacid tetrahydro-2H-pyran-4-yl ester (23.4 g, 45.9 mmol) andN,N-diisopropylethylamine (35.5 g, 275 mmol) in 150 ml of dry dimethylsulfoxide and 50 ml of dry dichloromethane. The mixture was stirred atthe same temperature for 1 hour. The reaction mixture was poured intoice-water and then extracted with dichloromethane. The organic layer waswashed with a 20% citric acid aqueous solution, a saturated sodiumhydrogen carbonate aqueous solution, and brine. After the organic layerwad dried over anhydrous sodium sulfate, the solvent was removed bydistillation in vacuo. Ethyl acetate was added to the residue andstirred overnight. The precipitated crystals were separated byfiltration to give 20.6 g (88%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.81 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.25-2.14(20H, m), 2.30-2.42 (1H, m), 3.22-3.34 (2H, m), 3.52 (2H, td, J=9 Hz, 3Hz), 3.85-3.98 (2H, m), 4.45 (1H, ddd, J=11 Hz, 6 Hz, 2 Hz), 4.79-4.88(1H, m), 4.93 (1H, s), 5.33 (1H, dd, J=8 Hz, 5 Hz), 6.31 (1H, t, J=6Hz), 7.27 (1H, d, J=8 Hz), 8.18 (1H, d, J=6 Hz)

To determine the Rf value, thin layer chromatography (TLC) analysis wasperformed under the conditions below. The Rf value shown in the examplebelow was also obtained under the same conditions.

TLC: HPTLC plates RP-18F254s manufactured by Merck KGaA

Developing solvent: acetonitrile:water=7:3

Rf value: 0.58

Production Example 5 Production of1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid

(1) Production of1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester

Benzyl 1-aminocyclohexanecarboxylate (9.27 g, 40 mmol) was added to adichloromethane solution of di-tert-butyl dicarbonate (8.7 g, 40 mmol)and 4-dimethylaminopyridine (488 mg, 4 mmol) and stirred at roomtemperature for 30 minutes. The reaction mixture was concentrated invacuo. To the residue were added1-tert-butoxycarbonyl-4-hydroxypiperidine (16 g, 80 mmol) andN,N-diisopropylethylamine (10.3 g, 80 mmol) and stirred at 100° C.overnight. The reaction mixture was returned to room temperature andthen diluted with ethyl acetate. The dilution was washed with a 10%potassium hydrogen sulfate aqueous solution, a saturated sodium hydrogencarbonate aqueous solution, and brine. After the organic layer was driedover anhydrous sodium sulfate, the solvent was removed by distillationin vacuo. The residue was purified by silica gel column chromatographyto give 16 g (87%) of the title compound.

¹H-NMR (CDCl₃, δ): 1.21-2.10 (14H, m), 1.46 (9H, s), 3.05-3.23 (2H, m),3.65 (2H, br-s), 4.67-4.80 (1H, m), 4.86 (1H, br-s), 5.13 (2H, s),7.23-7.40 (5H, m)

(2) Production of1-[[(4-piperidinyloxy)carbonyl]amino]cyclohexanecarboxylic acid benzylester hydrochloride

Four M hydrochloric acid/dioxane was added to1-[[[[1-[(1,1-dimethylethoxy)carbonyl]-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester (16 g, 34.7 mmol) and allowed to stand at roomtemperature for 2 hours. The reaction mixture was concentrated in vacuo.Ethyl acetate was added to the resulting residue. The resultingsuspension was stirred for 2 hours. The resulting crystals wereseparated by filtration and dried in vacuo to give 12 g (87%) of thetitle compound.

¹H-NMR (DMSO-d₆, δ): 1.12-1.30 (1H, m), 1.45-1.59 (5H, m), 1.60-1.78(4H, m), 1.83-2.02 (4H, m), 2.90-3.02 (2H, m), 3.05-3.20 (2H, m),4.65-4.74 (1H, m), 5.05 (2H, s), 7.28-7.42 (5H, m), 7.59 (1H, s)

(3) Production of1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester

Under ice cooling, methyl chloroformate (378 mg, 4.0 mmol) was added toa methylene chloride solution of1-[[(4-piperidinyloxy)carbonyl]amino]cyclohexanecarboxylic acid benzylester hydrochloride (1.59 g, 4.0 mmol) and triethylamine (2 g, 20 mmol).The mixture was stirred at room temperature overnight. Water was addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was separated and then washed with a 10%potassium hydrogen sulfate aqueous solution, a saturated sodium hydrogencarbonate aqueous solution, and brine. After the organic layer was driedover anhydrous sodium sulfate, the solvent was removed by distillationin vacuo. Diisopropyl ether was added to the resulting residue, and theresulting suspension was stirred overnight. The resulting crystals wereseparated by filtration and dried in vacuo to give 1.67 g (quantitative)of the title compound.

¹H-NMR (CDCl₃, δ): 1.21-2.11 (14H, m), 3.08-3.31 (2H, m), 3.51-3.79 (2H,m), 3.69 (3H, s), 4.65-4.82 (1H, m), 4.87 (1H, br-s), 5.31 (2H, s),7.12-7.39 (5H, m)

(4) Production of1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid

To an ethyl acetate solution of1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid benzyl ester (1.68 g, 4 mmol) was added 10% palladium-carbon (168mg) and stirred at room temperature under a hydrogen gas atmosphereovernight. The insoluble matter was removed by filtration, and thefiltrate was concentrated in vacuo. Diisopropyl ether was added to theresidue, and the resulting suspension was stirred overnight. Theresulting crystals were separated by filtration and dried in vacuo togive 1.01 g (75%) of the title compound.

¹H-NMR (CDCl₃, δ): 1.21-2.18 (14H, m), 3.26 (2H, br-s), 3.48 (1H, br-s),3.69 (3H, s), 3.61-3.89 (2H, m), 4.83 (1H, br-s), 4.94 (1H, br-s)

Production Example 6 Production of[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]carbamicacid 1-(methoxycarbonyl)-4-piperidinyl ester

Under ice cooling, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (316 mg, 1.65 mmol) was added to a methylene chloridesolution of1-[[[[1-(methoxycarbonyl)-4-piperidinyl]oxy]carbonyl]amino]cyclohexanecarboxylicacid (493 mg, 1.5 mmol),(2S,3S)-3-amino-N-[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]-2-hydroxy-4-methylpentanamide(386 mg, 1.5 mmol), and 1-hydroxybenzotriazole (241 mg, 1.57 mmol). Theliquid mixture was returned to room temperature and stirred overnight.The reaction mixture was diluted with methylene chloride. The dilutionwas washed with a 10% potassium hydrogen sulfate aqueous solution, asaturated sodium hydrogen carbonate aqueous solution, and brine. Afterthe organic layer was dried over anhydrous sodium sulfate, the solventwas removed by distillation in vacuo. Diisopropyl ether was added to theresulting residue, and the resulting suspension was stirred overnight.The resulting crystals were separated by filtration and dried in vacuoto give 795 mg (93%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.90 (3H, d, J=7 Hz), 1.00 (3H, d, J=7 Hz), 1.18-2.17(21H, m), 3.18-3.38 (4H, m), 3.68 (3H, s), 3.59-3.85 (1H, m), 3.92-4.05(1H, m), 4.18-4.28 (1H, m), 4.41-4.52 (1H, m), 4.60-4.73 (1H, m),4.73-4.85 (1H, m), 5.14 (1H, s), 6.20-6.31 (1H, m), 7.20 (1H, br-s),7.68 (1H, br-s)

Example 2 Production of[1-[[[(1S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-1-(1-methylethyl)-2,3-dioxopropyl]amino]carbonyl]cyclohexyl]carbamicacid 1-(methoxycarbonyl)-4-piperidinyl ester (compound 2)

To a dimethyl sulfoxide solution of[1-[[[(1S,2S)-3-[[(3S)-hexahydro-2-oxo-1H-azepin-3-yl]amino]-2-hydroxy-1-(1-methylethyl)-3-oxopropyl]amino]carbonyl]cyclohexyl]carbamicacid 1-(methoxycarbonyl)-4-piperidinyl ester (795 mg, 1.4 mmol) wasadded 2-iodoxybenzoic acid (1.96 g, 7.0 mmol). After the mixture wasstirred at room temperature for 2 hours, ethyl acetate and water wereadded to the reaction mixture. Sodium thiosulfate was then added to themixture until a clear solution was obtained. After the organic andaqueous layers were allowed to separate, the organic layer was washedsequentially with a saturated sodium hydrogen carbonate aqueous solutionand brine. After the resulting organic layer was dried over sodiumsulfate, the solvent was removed by distillation in vacuo. The resultingresidue was purified by silica gel column chromatography to give 516 mg(65%) of the title compound.

¹H-NMR (CDCl₃, δ): 0.79 (3H, d, J=7 Hz), 1.01 (3H, d, J=7 Hz), 1.20-2.21(20H, m), 2.30-2.41 (1H, m), 3.18-3.38 (4H, m), 3.67 (3H, s), 3.62-3.93(1H, m), 4.53 (1H, dd, J=10 Hz, 6 Hz), 4.78-4.90 (1H, m), 4.89 (1H, s),5.23-5.40 (1H, m), 6.02-6.18 (2H, m), 7.18-7.29 (1H, m), 8.17 (1H, d,J=6 Hz)

Rf value: 0.68

TEST EXAMPLES

As described below, cathepsin K inhibitory activity and bone resorptioninhibitory activity were measured according to the method shown in JP2000-204071 A. Comparative compounds 1 to 15 shown below are the top 15compounds showing good results among the cyclic amide derivativecompounds that are disclosed as having high bone resorption inhibitoryactivity in low-calcium diet mice in JP 2000-204071 A (Patent Literature1).

Comparative compound 1: the compound of Example 120 in Patent Literature1

Comparative compound 2: the compound of Example 5 in Patent Literature 1

Comparative compound 3: the compound of Example 140 in Patent Literature1

Comparative compound 4: the compound of Example 121 in Patent Literature1

Comparative compound 5: the compound of Example 82 in Patent Literature1

Comparative compound 6: the compound of Example 97 in Patent Literature1

Comparative compound 7: the compound of Example 92 in Patent Literature1

Comparative compound 8: the compound of Example 33 in Patent Literature1

Comparative compound 9: the compound of Example 131 in Patent Literature1

Comparative compound 10: the compound of Example 64 in Patent Literature1

Comparative compound 11: the compound of Example 34 in Patent Literature1

Comparative compound 12: the compound of Example 81 in Patent Literature1

Comparative compound 13: the compound of Example 6 in Patent Literature1

Comparative compound 14: the compound of Example 135 in PatentLiterature 1

Comparative compound 15: the compound of Example 27 in Patent Literature1

As to cathepsin K inhibitory activity, comparative compounds 1 to 15 andcompounds according to the present invention (compounds 1 and 2 shownbelow are the compounds obtained in Examples 1 and 2, respectively) weremeasured for IC₅₀ value (50% inhibitory concentration). As to boneresorption inhibitory activity, only the compounds of the presentinvention were subjected to the measurement, while the data shown in JP2000-204071 were used with respect to comparative compounds 1 to 15.

As to CYP3A4 inhibitory activity, comparative compounds 1 to 15 and thecompounds of the present invention were each measured for DI (directinhibition) and MBI (mechanism based inhibition), and the IC₅₀ value forDI and MBI was each calculated.

On the basis of these data, calculations were made to determine theratio (CYP/CatK) between the IC₅₀ values for CYP3A4 inhibitory activity(MBI) and the IC₅₀ values for cathepsin K inhibitory activity withrespect to the comparative compounds and the compounds of the presentinvention, and the selectivity for the target enzyme cathepsin K wasevaluated.

Test Example 1 Measurement of Cathepsin K Inhibitory Activity

Cathepsin K was prepared as follows. The proenzyme of cathepsin K wasproduced in cell culture media using a baculovirus expression system inSf21 insect cells and then incubated at 40° C. for 1 hour to form theactive enzyme (Tezuka et al., J. Biol. Chem., 269, 1106-1109 (1994)).The activity of cathepsin K was measured from the decomposition of thefluorescent substrate Z-Gly-Pro-Arg-MCA (3208-v from PEPTIDE INSTITUTE,INC.) according to the method of Aibe et al. (Aibe et al., Biol. Pharm.Bull., 19, 1026-1031 (1996)). Specifically, the decomposition of 20 μMZ-Gly-Pro-Arg-MCA by cathepsin K was measured in 100 mM potassium sodiumphosphate, 1 mM EDTA, 8 mM Cysteine, pH 6.0. The reaction was performedat 37° C. for 30 minutes and then quenched by the addition of 2×10⁻⁵ Mof calpeptin. After the reaction was quenched, the intensity offluorescence was measured at an excitation wavelength of 355 nm and ameasurement wavelength of 460 nm.

As to the measurement results, Tables 3 and 4 show the IC₅₀ values(nmol/L) of the comparative compounds and the compounds of the presentinvention, respectively, together with the results of other testexamples.

Test Example 2 Measurement of Bone Resorption Inhibitory Activity

The measurement was performed by the same method as described in JP2000-204071 A (Patent Literature 1). Specifically, male mice (23 to 25 gweight, 8 mice per group) were fed with low-calcium diet (0.1% calciumdiet) for 7 days. After overnight fasting, the compound of the presentinvention was orally administered to the mice at 100 mg/kg weight, and 4hours after the administration, the calcium concentration of the serumwas measured by the methyl xylenol blue method (Biochem Biophys ResCommun., 125, 441-447 (1984), FEBS Lett., 321(2-3), 247-250 (1993)). Therate (%) of decrease in serum calcium was determined by comparison withthe control group.

Tables 3 and 4 show the results of the measurement of the comparativecompounds and the compounds of the present invention, respectively,together with the results of other tests. It should be noted that thedata of the rate (%) of decrease in serum calcium as to comparativecompounds 1 to 15 are the values shown in JP 2000-204071 A (PatentLiterature 1).

Test Example 3 Measurement of CYP3A4 Inhibitory Activity

The measurement of CYP3A4 inhibitory activity was performed withreference to the method of Newton et al. (Drug Metab. Dispos. 23,154-158 (1995)) and the method described in JP 2007-236327 A.

A reaction mixture was prepared by mixing the compound of the presentinvention with midazolam as a typical substrate for CYP3A4 (see Food andDrug Administration (FDA) Guidance for Industry Drug InteractionStudies—Study Design, Data Analysis, Implications for Dosing, andLabeling Recommendations. FDA web site [online],www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm292362.pdf),coenzyme NADPH-generating system, human hepatic microsomes, and aphosphate buffer. The reaction mixture was incubated at 37° C. for 10minutes. Table 1 below shows the solutions used in the preparation ofthe coenzyme NADPH-generating system solution.

TABLE 1 Prepared Compound Name Solvent Concentration β-Nicotinamideadenine Phosphate Buffer 13 mmol/L dinucleotide phosphate (pH 7.4)(β-NADP⁺) glucose-6-phosphate Phosphate Buffer 33 mmol/L (G-6-P) (pH7.4) glucose-6-phosphate Phosphate Buffer 10 U/mL dehydrogenase (pH 7.4)(G-6-P DH(Y)) MgCl₂ Phosphate Buffer 33 mmol/L (pH 7.4)

The coenzyme NADPH-generating system solution was prepared by mixing thematerials shown in Table 1: the 13 mmol/L β-NADP⁺ solution, the 33mmol/L G-6-P solution, the solution of 10 U/mL G6PDH (Y) (manufacturedby Oriental Yeast Co., Ltd.), and the 33 mmol/L MgCl₂ solution in aratio of 1:1:0.4:1 (v:v:v:v). Table 2 below shows the composition of thereaction mixture used in the measurement of CYP3A4 inhibitory activity.The final concentrations of the compounds of the present invention andthe comparative compounds were set at the levels considered to benecessary for the calculation of the IC₅₀ values based on the results ofthe measurement performed at an arbitrary concentration in advance.

TABLE 2 Added Amount Solution (μL) Final Concentration InventiveCompound or 5 It was set at the level Comparative Compound necessary forthe calculation of the IC_(50c) value. Midazolam Solution 10 1000 nmol/L0.1M Phosphate Buffer 265 — (pH 7.4) Coenzyme NADPH- 170 β-NADP⁺ 1.3mmol/L Generating System G-6-P 3.3 mmol/L Solution G-6-P DH(Y) 0.4 U/mLMgCl₂ 3.3 mmol/L Diluted Microsomes 50 0.1 mg protein/mL

After the incubation, the reaction was quenched by the addition of anacetonitrile solution to the reaction mixture. The amount of1′-hydroxymidazolam produced (the metabolite produced from midazolam byCYP3A4) was measured in the quenched sample with a high-performanceliquid chromatography tandem mass spectrometer (LC-MS/MS). Each IC₅₀value for DI (direct inhibition) was determined from the amount of theproduced 1′-hydroxymidazolam and the final concentration of the compoundof the present invention or the comparative compound in the reactionmixture.

MBI (mechanism based inhibition) was evaluated as follows. After thereaction mixture not containing midazolam (but containing the compoundof the present invention or the comparative compound, the coenzymeNADPH-generating system, the human hepatic microsomes, and the phosphatebuffer) was pre-incubated at 37° C. for 30 minutes, midazolam was addedto the reaction mixture. The reaction mixture was then incubated at 37°C. for 10 minutes. Subsequently, the reaction was quenched by theaddition of an acetonitrile solution to the reaction mixture. The amountof 1′-hydroxymidazolam produced was measured in the quenched sample withan LC-MS/MS. As in the case of DI, each IC₅₀ value for MBI wasdetermined from the amount of the produced 1′-hydroxymidazolam and thefinal concentration of the compound of the present invention or thecomparative compound in the reaction mixture.

Tables 3 and 4 show the results of the measurement of the comparativecompounds and the compounds of the present invention, respectively,together with the results of other tests.

TABLE 3 Rate of CatK CYP3A4 Inhibitory Com- Decrease in Inhibitory IC₅₀parative Serum Ca IC₅₀ (μmol/L) CYP/ Compound (%) (nmol/L) DI MBI CatK 15.39 16 11.7 3.36 207 2 4.71 13 9.31 1.53 122 3 4.50 3.4 0.180 0.0373 114 4.48 7.4 12.6 2.16 291 5 4.38 26 14.0 4.59 179 6 4.33 20 8.28 2.07 1037 4.08 23 23.7 4.41 193 8 4.07 7.8 15.5 2.57 328 9 3.97 39 0.723 0.09242 10 3.60 16 15.5 3.85 246 11 3.50 5.4 10.8 2.07 384 12 3.50 3.6 5.230.985 274 13 3.46 6 2.78 2.23 370 14 3.37 4.8 0.994 0.152 31 15 3.26 1216.0 4.97 401

TABLE 4 Rate of CatK CYP3A4 Decrease in Inhibitory Inhibitory InventiveSerum Ca IC₅₀ C₅₀ (μmol/L) CYP/ Compound (%) (nmol/L) DI MBI CatKCompound 1 6.2 0.56 >100 80.0 141739 Compound 2 5.6 0.52 55.6 23.0 44231

These results show that all the comparative compounds have an IC₅₀ value(MBI) of less than 10 μM for CYP3A4 inhibition whereas the compounds ofthe present invention have an IC₅₀ value of more than 20 μM for CYP3A4inhibition.

Therefore, according to the above-mentioned classification of theintensity of CYP3A4 inhibition, all the comparative compounds aredetermined to have at least a medium level of CYP3A4 inhibitoryactivity, whereas the compounds of the present invention are determinedto have a low level of CYP3A4 inhibitory activity.

The enzyme selectivity (CYP/CatK) of the compounds of the presentinvention is calculated to be a value of more than 40,000 whereas thatof the comparative compounds is calculated to be a value of less thanabout 400.

The invention claimed is:
 1. A compound of formula (I):

wherein X is —O— or —N(R¹)—, wherein R¹ is a (C1 to C10 alkoxy)carbonylgroup.
 2. The compound according to claim 1, wherein in formula (I), Xis —O—.
 3. The compound according to claim 1, wherein in formula (I), Xis —N(R¹)—, wherein R¹ is a (C1 to C10 alkoxy)carbonyl group.
 4. Thecompound according to claim 3, wherein R¹ is a methoxycarbonyl group. 5.A pharmaceutical composition comprising the compound according to claim1 and a pharmaceutically acceptable carrier.